iPSC 衍生髓系细胞递送 I 型干扰素通过 XCR1 树突状细胞引发抗肿瘤免疫。

Type I Interferon Delivery by iPSC-Derived Myeloid Cells Elicits Antitumor Immunity via XCR1 Dendritic Cells.

机构信息

Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa 277-8577, Japan; Department of Gastroenterological Surgery, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan.

Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa 277-8577, Japan; Division of Immunology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan.

出版信息

Cell Rep. 2019 Oct 1;29(1):162-175.e9. doi: 10.1016/j.celrep.2019.08.086.

DOI:10.1016/j.celrep.2019.08.086

PMID:31577946

Abstract

Type I interferons (IFNs) play important roles in antitumor immunity. We generated IFN-α-producing cells by genetically engineered induced pluripotent stem cell (iPSC)-derived proliferating myeloid cells (iPSC-pMCs). Local administration of IFN-α-producing iPSC-pMCs (IFN-α-iPSC-pMCs) alters the tumor microenvironment and propagates the molecular signature associated with type I IFN. The gene-modified cell actively influences host XCR1 dendritic cells to enhance CD8 T cell priming, resulting in CXCR3-dependent and STING-IRF3 pathway-independent systemic tumor control. Administration of IFN-α-iPSC-pMCs in combination with immune checkpoint blockade overcomes resistance to single-treatment modalities and generates long-lasting antitumor immunity. These preclinical data suggest that IFN-α-iPSC-pMCs might constitute effective immune-stimulating agents for cancer that are refractory to checkpoint blockade.

摘要

I 型干扰素 (IFN) 在抗肿瘤免疫中发挥重要作用。我们通过基因工程诱导多能干细胞 (iPSC) 衍生的增殖髓样细胞 (iPSC-pMC) 产生 IFN-α。局部给予 IFN-α 产生的 iPSC-pMC（IFN-α-iPSC-pMC）可改变肿瘤微环境并传播与 I 型 IFN 相关的分子特征。基因修饰的细胞可主动影响宿主 XCR1 树突状细胞，增强 CD8 T 细胞的启动，从而导致 CXCR3 依赖性和 STING-IRF3 途径非依赖性的全身性肿瘤控制。IFN-α-iPSC-pMC 联合免疫检查点阻断的给药可克服对单一治疗方式的耐药性，并产生持久的抗肿瘤免疫。这些临床前数据表明，IFN-α-iPSC-pMC 可能是对抗对检查点阻断耐药的癌症的有效免疫刺激剂。